Process for removing bile salts from a patient and alkylated compositions therefor

ABSTRACT

The invention relates to a method for removing bile salts from a patient in need thereof and compositions useful in the method. The method comprises administering to the patient a therapeutically effective amount of a salt of an alkylated and crosslinked polymer. The alkylated and crosslinked polymer salt comprises the reaction product of crosslinked polymers, or salts and copolymers thereof having amine containing repeat units, with at least one aliphatic alkylating agent.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Ser. No. 09/532,984filed Mar. 22, 2000, which is a continuation of U.S. Ser. No. 09/388,876filed Sep. 2, 1999, now U.S. Pat. No. 6,066,678, which is a continuationof U.S. Ser. No. 09/288,357 filed Apr. 8, 1999, now U.S. Pat. No.5,981,693, which is a continuation of U.S. Ser. No. 09/129,286 filedAug. 5, 1998, now U.S. Pat. No. 5,917,007, which is a continuation ofU.S. Ser. No. 08/910,692 filed Aug. 13, 1997, now abandoned, which is adivisional of U.S. Ser. No. 08/460,980 filed on Jun. 5, 1995, now U.S.Pat. No. 5,679,717, which is a continuation-in-part of U.S. Ser. No.08/258,431 filed Jun. 10, 1994, now abandoned, the entire teachings ofall of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] This invention relates to removing bile salts from a patient.

[0003] Salts of bile acids act as detergents to solubilize andconsequently aid in digestion of dietary fats. Bile acids are precursorsto bile salts, and are derived from cholesterol. Following digestion,bile acids can be passively absorbed in the jejunum, or, in the case ofconjugated primary bile acids, reabsorbed by active transport in theileum. Bile acids which are not reabsorbed by active transport aredeconjugated and dehydroxylated by bacterial action in the distal ileumand large intestine.

[0004] Reabsorption of bile acids from the intestine conserveslipoprotein cholesterol in the bloodstream. Conversely, bloodcholesterol level can be diminished by reducing reabsorption of bileacids.

[0005] One method of reducing the amount of bile acids that arereabsorbed is oral administration of compounds that sequester the bileacids and cannot themselves be absorbed. The sequestered bile acidsconsequently either decompose by bacterial action or are excreted.

[0006] Many bile acid sequestrants, however, bind relatively hydrophobicbile acids more avidly than conjugated primary bile acids, such asconjugated cholic and chenodeoxycholic acids. Further, active transportin the ileum causes substantial portions of sequestered conjugatedprimary bile acids to be desorbed and to enter the free bile acid poolfor reabsorption. In addition, the volume of sequestrants that can beingested safely is limited. As a result, the effectiveness ofsequestrants to diminish blood cholesterol levels is also limited.

[0007] Sequestering and removing bile salts (e.g., cholate,glycocholate, glycochenocholate, taurocholate, and deoxycholate salts)in a patient can be used to reduce the patient's cholesterol level.Because the biological precursor to bile salt is cholesterol, themetabolism of cholesterol to make bile salts is accompanied by asimultaneous reduction in the cholesterol in the patient.

[0008] Cholestyramine, a polystyrene/divinylbenzene ammonium ionexchange resin, when ingested, removes bile salts via the digestivetract. This resin, however, is unpalatable, gritty and constipating.Resins which avoid (totally or partially) these disadvantages and/orpossess improved bile salt sequestration properties are needed.

SUMMARY OF THE INVENTION

[0009] The invention relates to the discovery that a new class of ionexchange resins have improved bile salt sequestration properties andlittle to no grittiness, thereby improving the palatability of thecomposition.

[0010] The resins comprise cross-linked polyamines which arecharacterized by one or more hydrophobic substituents and, optionally,one or more quaternary ammonium containing substituents.

[0011] In general, the invention features resins and their use inremoving bile salts from a patient that includes administering to thepatient a therapeutically effective amount of the reaction product of:

[0012] (a) one or more crosslinked polymers, salts and copolymersthereof characterized by a repeat unit selected from the groupconsisting essentially of:

 (NR—CH₂CH₂)_(n)  (3)

(NR—CH₂CH₂—NR—CH₂CH₂—NR—CH₂CHOH—CH₂)_(n)  (4)

[0013] where n is a positive integer and each R, independently, is H ora substituted or unsubstituted alkyl group (e.g., C₁-C₈ alkyl); and

[0014] (b) at least one alkylating agent. The reaction product ischaracterized in that: (i) at least some of the nitrogen atoms in therepeat units are unreacted with the alkylating agent; (ii) less than 10mol % of the nitrogen atoms in the repeat units that react with thealkylating agent form quaternary ammonium units; and (iii) the reactionproduct is preferably non-toxic and stable once ingested.

[0015] Suitable substituents include quaternary ammonium, amine,alkylamine, dialkylamine, hydroxy, alkoxy, halogen, carboxamide,sulfonamide and carboxylic acid ester, for example.

[0016] In preferred embodiments, the polyamine of compound (a) of thereaction product is crosslinked by means of a multifunctionalcrosslinking agent, the agent being present in an amount from about0.5-25% (more preferably about 2.5-20% (most preferably 1-10%)) byweight, based upon total weight or monomer plus crosslinking agent. Apreferred crosslinking agent is epichlorohydrin because of its highavailability and low cost. Epichlorohydrin is also advantageous becauseof it's low molecular weight and hydrophilic nature, increasing thewater-swellability and gel properties of the polyamine.

[0017] The invention also features compositions based upon theabove-described reaction products.

[0018] The invention provides an effective treatment for removing bilesalts from a patient (and thereby reducing the patient's cholesterollevel). The compositions are non-toxic and stable when ingested intherapeutically effective amounts.

[0019] Other features and advantages will be apparent from the followingdescription of the preferred embodiments thereof and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Compositions

[0021] Preferred reaction products include the products of one or morecrosslinked polymers having the formulae set forth in the Summary of theInvention, above, and one or more alkylating agents. The polymers arecrosslinked. The level of crosslinking makes the polymers completelyinsoluble and thus limits the activity of the alkylated reaction productto the gastrointestinal tract only. Thus, the compositions arenon-systemic in their activity and will lead to reduced side-effects inthe patient.

[0022] By “non-toxic” it is meant that when ingested in therapeuticallyeffective amounts neither the reaction products nor any ions releasedinto the body upon ion exchange are harmful. Cross-linking the polymerrenders the polymer substantially resistant to absorption. When thepolymer is administered as a salt, the cationic counterions arepreferably selected to minimize adverse effects on the patient, as ismore particularly described below.

[0023] By “stable” it is meant that when ingested in therapeuticallyeffective amounts the reaction products do not dissolve or otherwisedecompose in vivo to form potentially harmful by-products, and remainsubstantially intact so that they can transport material out of thebody.

[0024] By “salt” it is meant that the nitrogen group in the repeat unitis protonated to create a positively charged nitrogen atom associatedwith a negatively charged countenon.

[0025] By “alkylating agent” it is meant a reactant which, when reactedwith the crosslinked polymer, causes an alkyl group or derivativethereof (e.g., a substituted alkyl, such as an aralkyl, hydroxyalkyl,alkylammonium salt, alkylamide, or combination thereof) to be covalentlybound to one or more of the nitrogen atoms of the polymer.

[0026] One example of preferred polymer is characterized by a repeatunit having the formula

[0027] or a salt or copolymer thereof; wherein x is zero or an integerbetween about 1 to 4.

[0028] A second example of a preferred polymer is characterized by arepeat unit having the formula

(NH—CH₂CH₂)_(n)  (6)

[0029] or a salt or copolymer thereof.

[0030] A third example of a preferred polymer is characterized by arepeat unit having the formula

(NH—CH₂CH₂—NH—CH₂CH₂—NH—CH₂CHOH—CH₂)_(n)  (7)

[0031] or a salt or copolymer thereof.

[0032] The polymers are preferably crosslinked prior to alkylation.Examples of suitable crosslinking agents include acryloyl chloride,epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether,and dimethyl succinate. The amount of crosslinking agent is typicallybetween 0.5 and 25 weight %, based upon combined weight of crosslinkingagent and monomer, with 2.5-20%, or 1-10%, being preferred.

[0033] Typically, the amount of crosslinking agent that is reacted withthe amine polymer is sufficient to cause reaction of between about 0.5and twenty percent of the amines. In a preferred embodiment, betweenabout 0.5 and six percent of the amine groups react with thecrosslinking agent.

[0034] Crosslinking of the polymer can be achieved by reacting thepolymer with a suitable crosslinking agent in an aqueous causticsolution at about 25° C. for a period of time of about eighteen hours tothereby form a gel. The gel is then combined with water and blended toform a particulate solid. The particulate solid can then be washed withwater and dried under suitable conditions, such as a temperature ofabout 50° C. for a period of time of about eighteen hours.

[0035] Alkylation involves reaction between the nitrogen atoms of thepolymer and the alkylating agent (which may contain additional nitrogenatoms, e.g., in the form of amido or ammonium groups). In addition, thenitrogen atoms which do react with the alkylating agent(s) resistmultiple alkylation to form quaternary ammonium ions such that less than10 mol % of the nitrogen atoms form quaternary ammonium ions at theconclusion of alkylation.

[0036] Preferred alkylating agents have the formula RX where R is aC₁-C₂₀ alkyl (preferably C₄-C₂₀), C₁-C₂₀ hydroxy-alkyl (preferablyC₄-C₂₀ hydroxyalkyl), C₇-C₂₀ aralkyl, C₁-C₂₀ alkylammonium (preferablyC₄-C₂₀ alkyl ammonium), or C₁-C₂₀ alkylamido (preferably C₄-C₂₀ alkylamido) group and X includes one or more electrophilic leaving groups. By“electrophilic leaving group” it is meant a group which is displaced bya nitrogen atom in the crosslinked polymer during the alkylationreaction. Examples of preferred leaving groups include halide, epoxy,tosylate, and mesylate group. In the case of, e.g., epoxy groups, thealkylation reaction causes opening of the three-membered epoxy ring.

[0037] Examples of preferred alkylating agents include a C₁-C₂₀ alkylhalide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decylhalide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, andcombinations thereof); a C₁-C₂₀ dihaloalkane (e.g., a1,10-dihalodecane); a C₁-C₂₀ hydroxyalkyl halide (e.g., an11-halo-1-undecanol); a C₁-C₂₀ aralkyl halide (e.g., a benzyl halide); aC₁-C₂₀ alkyl halide ammonium salt (e.g., a (4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt,(8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammoniumsalt, (12-halododecyl)-trimethylammonium salts and combinationsthereof); a C₁-C₂₀ alkyl epoxy ammonium salt (e.g., a(glycidylpropyl)-trimethylammonium salt); and a C₁-C₂₀ epoxy alkylamide(e.g., an N-(2,3-eoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, and combinations thereof).

[0038] It is particularly preferred to react the polymer with at leasttwo alkylating agents, added simultaneously or sequentially to thepolymer. In one preferred example, one of the alkylating agents has theformula RX where R is a C₁-C₂₀ alkyl group and X includes one or moreelectrophilic leaving groups (e.g., an alkyl halide), and the otheralkylating agent has the formula R′X where R′ is a C₁-C₂₀ alkyl ammoniumgroup and X includes one or more electrophilic leaving groups (e.g., analkyl halide ammonium salt).

[0039] In another preferred example, one of the alkylating agents hasthe formula RX where R is a C₁-C₂₀ alkyl group and X includes one ormore electrophilic leaving groups (e.g., an alkyl halide), and the otheralkylating agent has the formula R′X where R′ is a C₁-C₂₀ hydroxyalkylgroup and X includes one or more electrophilic leaving groups (e.g., ahydroxy alkyl halide).

[0040] In another preferred example, one of the alkylating agents is aC₁-C₂₀ dihaloalkane and the other alkylating agent is a C₁-C₂₀alkylammonium salt.

[0041] The reaction products may have fixed positive charges, or mayhave the capability of becoming charged upon ingestion at physiologicalpH. In the latter case, the charged ions also pick up negatively chargedcounterions upon ingestion that can be exchanged with bile salts. In thecase of reaction products having fixed positive charges, however, thereaction product may be provided with one or more exchangeablecounterions. Examples of suitable counterions include Cl⁻, Br⁻, CH₃0SO₃⁻, HSO₄ ⁻, SO₄ ²⁻, HCO₃ ⁻, CO₃ ⁻, acetate, lactate, succinate,propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acidderivative, a nucleotide, a lipid, or a phospholipid. The counterionsmay be the same as, or different from, each other. For example, thereaction product may contain two different types of counterions, both ofwhich are exchanged for the bile salts being removed. More than onereaction product, each having different counterions associated with thefixed charges, may be administered as well.

[0042] The alkylating agent can be added to the cross-linked polymer ata molar ratio between about 0.05:1 to 4:1, for example, the alkylatingagents can be preferably selected to provide hydrophobic regions andhydrophilic regions.

[0043] The amine polymer is typically alkylated by combining the polymerwith the alkylating agents in an organic solvent. The amount of firstalkylating agent combined with the amine polymer is generally sufficientto cause reaction of the first alkylating agent with between about 5 and75 of the percent of amine groups on the amine polymer that areavailable for reaction. The amount of second alkylating agent combinedwith the amine polymer and solution is generally sufficient to causereaction of the second alkylating agent with between about 5 and about75 of the amine groups available for reaction on the amine polymer.Examples of suitable organic solvents include methanol, ethanal,isopropanol, acetonitrile, DMF and DMSO. A preferred organic solvent ismethanol.

[0044] In one embodiment, the reaction mixture is heated over a periodof about forty minutes to a temperature of about 65° C., with stirring.Typically, an aqueous sodium hydroxide solution is continuously addedduring the reaction period. Preferably, the reaction period at 65° C. isabout eighteen hours, followed by gradual cooling to a room temperatureof about 25° C. over a period of about four hours. The resultingreaction product is then filtered, resuspended in methanol, filteredagain, and then washed with a suitable aqueous solution, such as twomolar sodium chloride, and then with deionized water. The resultantsolid product is then dried under suitable conditions, such as at atemperature of about 60° C. in an air-drying oven. The dried solid canthen be subsequently processed. Preferably, the solid is ground andpassed through an 80 mesh sieve.

[0045] In a particularly preferred embodiment of the invention, theamine polymer is a crosslinked poly(allylamine), wherein the firstsubstituent includes a hydrophobic decyl moiety, and the second aminesubstituent includes a hexyltrimethylammonium. Further, the particularlypreferred crosslinked poly(allylamine) is crosslinked by epichlorohydrinthat is present in a range of between about two and six percent of theamines available for reaction with the epichlorohydrin.

[0046] The invention will now be described more specifically by theexamples.

EXAMPLES

[0047] A. Polymer Preparation

[0048] 1. Preparation of Poly (vinylamine)

[0049] The first step involved the preparation ofethylidenebisacetamide. Acetamide (118 g), acetaldehyde (44.06 g),copper acetate (0.2 g), and water (300 mL) were placed in a 1 L threeneck flask fitted with condenser, thermometer, and mechanical stirred.Concentrated HCl (34 mL) was added and the mixture was heated to 45-50°C. with stirring for 24 hours. The water was then removed in vacuo toleave a thick sludge which formed crystals on cooling to 5° C. Acetone(200 mL) was added and stirred for a few minutes, after which the solidwas filtered off and discarded. The acetone was cooled to 0° C. andsolid was filtered off. This solid was rinsed in 500 mL acetone and airdried 18 hours to yield 31.5 g of ethylidenebis-acetamide.

[0050] The next step involved the preparation of vinylacetamide fromethylidenebisacetamide. Ethylidenebisacetamide (31.05 g), calciumcarbonate (2 g) and celite 541 (2 g) were placed in a 500 mL three neckflask fitted with a thermometer, a mechanical stirred, and a distillingheat atop a Vigroux column. The mixture was vacuum distilled at 24 mm Hgby heating the pot to 180-225° C. Only a single fraction was collected(10.8 g) which contained a large portion of acetamide in addition to theproduct (determined by NMR). This solid product was dissolved inisopropanol (30 mL) to form the crude vinylacetamide solution used forpolymerization.

[0051] Crude vinylacetamide solution (15 mL), divinylbenzene (1 g,technical grade, 55% pure, mixed isomers), and AIBN (0.3 g) were mixedand heated to reflux under a nitrogen atmosphere for 90 minutes, forminga solid precipitate. The solution was cooled, isopropanol (50 mL) wasadded, and the solid was collected by centrifugation. The solid wasrinsed twice in isopropanol, once in water, and dried in a vacuum ovento yield 0.8 g of poly(vinylacetamide), which was used to preparepoly(vinylamine as follows).

[0052] Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neckflask containing water (25 mL) and conc. HCl (25 mL). The mixture wasrefluxed for 5 days, after which the solid was filtered off, rinsed oncein water, twice in isopropanol, and dried in a vacuum oven to yield 0.77g of product. Infrared spectroscopy indicated that a significant amountof the amide (1656 cm⁻¹) remained and that not much amine (1606 cm⁻¹)was formed. The product of this reaction (˜0.84 g) was suspended in NaOh(46 g) and water (46 g) and heated to boiling (˜140° C.). Due to foamingthe temperature was reduced and maintained at ˜100° C. for 2 hours.Water (100 mL) was added and the solid collected by filtration. Afterrinsing once in water the solid was suspended in water (500 mL) andadjusted to pH 5 with acetic acid. The solid was again filtered off,rinsed with water, then isopropanol, and dried in a vacuum oven to yield0.51 g of product. Infrared spectroscopy indicated that significantamine had been formed.

[0053] 2. Preparation of Poly(ethyleneimine)

[0054] Polyethyleneimine (120 g of a 50% aqueous solution; ScientificPolymer Products) was dissolved in water (250 mL). Epichlorohydrin (22.1mL) was added dropwise. The solution was heated to 60° C. for 4 hours,after which it had gelled. The gel was removed, blended with water (1.5L) and the solid was filtered off, rinsed three times with water (3 L)and twice with isopropanol (3 L), and the resulting gel was dried in avacuum oven to yield 81.2 g of the title polymer.

[0055] 3. Preparation of Poly(allylamine) Hydrochloride

[0056] To a 2 liter, waterjacketed reaction kettle equipped with (1) acondenser topped with a nitrogen gas inlet, (2) a thermometer, and (3) amechanical stirrer was added concentrated hydrochloric acid (360 mL).The acid was cooled to 5° C. using circulating water in the jacket ofthe reaction kettle (water temperature=0° C.). Allylamine (328.5 mL, 250g) was added dropwise with stirring while maintaining the reactiontemperature at 5-10° C. After addition was complete, the mixture wasremoved, placed in a 3 liter one-neck flask, and 206 g of liquid wasremoved by rotary vacuum evaporation at 60° C. Water (20 mL) was thenadded and the liquid was returned to the reaction kettle.Azobis(amidinopropane) dihydrochloride (0.5 g) suspended in 11 mL ofwater was then added. The resulting reaction mixture was heated to 50°C. under a nitrogen atmosphere with stirring for 24 hours. Additionalazobis(amidinopropane) dihydrochloride (5 mL) suspended in 11 mL ofwater was then added, after which heating and stirring were continuedfor an additional 44 hours.

[0057] At the end of this period, distilled water (100 mL) was added tothe reaction mixture and the liquid mixture allowed to cool withstirring. The mixture was then removed and placed in a 2 literseparatory funnel, after which it was added dropwise to a stirringsolution of methanol (4 L), causing a solid to form. The solid wasremoved by filtration, re-suspended in methanol (4 L), stirred for 1hour, and collected by filtration. The methanol rinse was then repeatedone more time and the solid dried in a vacuum oven to afford 215.1 g ofpoly(allylamine) hydrochloride as a granular white solid.

[0058] 4. Preparation of Poly(allylamine) Hydrochloride Crosslinked withEpichlorohydrin

[0059] To a 5 gallon vessel was added poly(allylamine) hydrochlorideprepared as described in Example 3 (1 kg) and water (4 L). The mixturewas stirred to dissolve the hydrochloride and the pH was adjusted byadding solid NaOH (284 g). The resulting solution was cooled to roomtemperature, after which epichlorohydrin crosslinking agent (50 mL) wasadded all at once with stirring. The resulting mixture was stirredgently until it gelled (about 35 minutes). The crosslinking reaction wasallowed to proceed for an additional 18 hours at room temperature, afterwhich the polymer gel was removed and placed in portions in a blenderwith a total of 10 L of water. Each portion was blended gently for about3 minutes to form coarse particles which were then stirred for 1 hourand collected by filtration. The solid was rinsed three times bysuspending it in water (10 L, 15 L, 20 L), stirring each suspension for1 hour, and collecting the solid each time by filtration. The resultingsolid was then rinsed once by suspending it in isopropanol (17 L),stirring the mixture for 1 hour, and then collecting the solid byfiltration, after which the solid was dried in a vacuum oven at 50° C.for 18 hours to yield about 677 g of the cross linked polymer as agranular, brittle, white solid.

[0060] 5. Preparation of Poly(allylamine) Hydrochloride Crosslinked withButanedioldiglycidyl Ether

[0061] To a 5 gallon plastic bucket was added poly(allylamine)hydrochloride prepared as described in Example 3 (500 g) and water (2L). The mixture was stirred to dissolve the hydrochloride and the pH wasadjusted to 10 by adding solid NaOH (134.6 g). The resulting solutionwas cooled to room temperature in the bucket, after which1,4-butanedioldiglycidyl ether crosslinking agent (65 mL) was added allat once with stirring. The resulting mixture was stirred gently until itgelled (about 6 minutes). The crosslinking reaction was allowed toproceed for an additional 18 hours at room temperature, after which thepolymer gel was removed and dried in a vacuum oven at 75° C. for 24hours. The dry solid was then ground and sieved to −30 mesh, after whichit was suspended in 6 gallons of water and stirred for 1 hour. The solidwas then filtered off and the rinse process repeated two more times. Theresulting solid was then air dried for 48 hours, followed by drying in avacuum oven at 50° C. for 24 hours to yield about 415 g of thecrosslinked polymer as a white solid.

[0062] 6. Preparation of Poly(allylamine) Hydrochloride Crosslinked withEthanedioldiglycidyl Ether

[0063] To a 100 mL beaker was added poly(allylamine) hydrochlorideprepared as described in Example 3 (10 g) and water (40 mL). The mixturewas stirred to dissolve the hydrochloride and the pH was adjusted to 10by adding solid NaOH. The resulting solution was cooled to roomtemperature in the beaker, after which 1,2-ethanedioldiglycidyl ethercrosslinking agent (2.0 mL) was added all at once with stirring. Theresulting mixture was stirred gently until it gelled (about 4 minutes).The crosslinking reaction was allowed to proceed for an additional 18hours at room temperature, after which the polymer gel was removed andblended in 500 mL of methanol. The solid was then filtered off andsuspended in water (500 mL). After stirring for 1 hour, the solid wasfiltered off and the rinse process repeated. The resulting solid wasrinsed twice in isopropanol (400 mL) and then dried in a vacuum oven at50° C. for 24 hours to yield 8.7 g of the crosslinked polymer as a whitesolid.

[0064] 7. Preparation of Poly(allylamine) Hydrochloride Crosslinked withDimethylsuccinate

[0065] To a 500 mL round bottom flask was added poly(allylamine)hydrochloride prepared as described in Example 3 (10 g), methanol (100mL), and triethylamine (10 mL). The mixture was stirred anddimethylsuccinate crosslinking agent (1 mL) was added. The solution washeated to reflux and the stirring discontinued after 30 minutes. After18 hours, the solution was cooled to room temperature, and the solidfiltered off and blended in 400 mL of isopropanol. The solid was thenfiltered off and suspended in water (1 L). After stirring for 1 hour,the solid was filtered off and the rinse process repeated two moretimes. The solid was then rinsed once in isopropanol (800 mL) and driedin a vacuum oven at 50° C. for 24 hours to yield 5.9 g of thecrosslinked polymer as a white solid.

[0066] 8. Preparation of Poly(ethyleneimine) Crosslinked with AcryloylChloride

[0067] Into a 5 L three neck flask equipped with a mechanical stirred, athermometer, and an addition funnel was added poly(ethyleneimine) (510 gof a 50% aqueous solution, equivalent to 255 g of dry polymer) andisopropanol (2.5 L). Acryloyl chloride crosslinking agent (50 g) wasadded dropwise through the addition funnel over a 35 minute period whilemaintaining the temperature below 29° C. The solution was then heated to60° C. with stirring for 18 hours, after which the solution was cooledand the solid immediately filtered off. The solid was then washed threetimes by suspending it in water (2 gallons), stirring for 1 hour, andfiltering to recover the solid. Next, the solid was rinsed once bysuspending it in methanol (2 gallons), stirring for 30 minutes, andfiltering to recover the solid. Finally, the solid was rinsed inisopropanol as in Example 7 and dried in a vacuum oven at 50° C. for 18hours to yield 206 g of the crosslinked polymer as a light orangegranular solid.

[0068] 9. Alkylation of Poly(allylamine) Crosslinked withButanedioldiglydicyl Ether with 1-iodooctane Alkylating Agent

[0069] Poly(allylamine) crosslinked with butanedioldiglycidyl etherprepared as described in Example 5 (5 g) was suspended in methanol (100mL) and sodium hydroxide (0.2 g) was added. After stirring for 15minutes, 1-iodooctane (1.92 mL) was added and the mixture stirred at 60°C. for 20 hours. The mixture was then cooled and the solid filtered off.Next, the solid was washed by suspending it in isopropanol (500 mL),after which it was stirred for 1 hour and then collected by filtration.The wash procedure was then repeated twice using aqueous sodium chloride(500 mL of a 1 M solution), twice with water (500 mL), and once withisopropanol (500 mL) before drying in a vacuum oven at 50° C. for 24hours to yield 4.65 g of alkylated product.

[0070] The procedure was repeated using 2.88 mL of 1-iodooctane to yield4.68 g of alkylated product.

[0071] 10. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodooctane Alkylating Agent

[0072] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (5 g) was alkylated according to the proceduredescribed in Example 9 except that 3.84 mL of 1-iodooctane was used. Theprocedure yielded 5.94 g of alkylated product.

[0073] 11. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodooctadecane Alkylating Agent

[0074] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (10 g) was suspended in methanol (100 mL) andsodium hydroxide (0.2 g) was added. After stirring for 15 minutes,1-iodooctadecane (8.1 g) was added and the mixture stirred at 60° C. for20 hours. The mixture was then cooled and the solid filtered off. Next,the solid was washed by suspending it in isopropanol (500 mL), afterwhich it was stirred for 1 hour and then collected by filtration. Thewash procedure was then repeated twice using aqueous sodium chloride(500 mL of a 1 M solution), twice with water (500 mL), and once withisopropanol (500 mL) before drying in a vacuum oven at 50° C. for 24hours to yield 9.6 g of alkylated product.

[0075] 12. Alkylation of Poly(allylamine) Crosslinked withButanedioldiglycidyl Ether with 1-iodododecane Alkylating Agent

[0076] Poly(allylamine) crosslinked with butanedioldiglycidyl etherprepared as described in Example 5 (5 g) was alkylated according to theprocedure described in Example 11 except that 2.47 mL of 1-iodododecanewas used. The procedure yielded 4.7 g of alkylated product.

[0077] 13. Alkylation of Poly(allylamine) Crosslinked withButanedioldiglycidyl Ether with Benzyl Bromide Alkylating Agent

[0078] Poly(allylamine) crosslinked with butanedioldiglycidyl etherprepared as described in Example 5 (5 g) was alkylated according to theprocedure described in Example 11 except that 2.42 mL of benzyl bromidewas used. The procedure yielded 6.4 g of alkylated product.

[0079] 14. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with Benzyl Bromide Alkylating Agent

[0080] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (5 g) was alkylated according to the proceduredescribed in Example 11 except that 1.21 mL of benzyl bromide was used.The procedure yielded 6.6 g of alkylated product.

[0081] 15. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iododecane Alkylating Agent

[0082] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (20 g) was alkylated according to the proceduredescribed in Example 11 except that 7.15 g of 1-iododecane and 2.1 g ofNaOH were used. The procedure yielded 20.67 g of alkylated product.

[0083] 16. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodobutane Alkylating Agent

[0084] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (20 g) was alkylated according to the proceduredescribed in Example 11 except that 22.03 g of 1-iodobutane and 8.0 g ofNaOH were used. The procedure yielded 24.0 g of alkylated product.

[0085] The procedure was also followed using 29.44 g and 14.72 g of1-iodobutane to yield 17.0 g and 21.0 g, respectively, of alkylatedproduct.

[0086] 17. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodotetradecane Alkylating Agent

[0087] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (5 g) was alkylated according to the proceduredescribed in Example 11 except that 2.1 mL of 1-iodotetradecane wasused. The procedure yielded 5.2 g of alkylated product.

[0088] The procedure was also followed using 6.4 mL of 1-iodotetradecaneto yield 7.15 g of alkylated product.

[0089] 18. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodooctane Alkylating Agent

[0090] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 8 (5 g) was alkylated according to the proceduredescribed in Example 11 except that 1.92 mL of 1-iodooctane was used.The procedure yielded 5.0 g of alkylated product.

[0091] 19. Alkylation of a Copolymer of Diethylene Triamine andEpichlorohydrin with 1-iodooctane Alkylating Agent

[0092] A copolymer of diethylene triamine and epichlorohydrin (10 g) wasalkylated according to the procedure described in Example 11 except that1.92 mL of 1-iodooctane was used. The procedure yielded 5.3 g ofalkylated product.

[0093] 20. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 1-iodododecane and Glycidyl-propyltrimethylammoniumChloride Alkylating Agents

[0094] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (20 g) was alkylated according to the proceduredescribed in Example 11 except that 23.66 g of 1-iodododecane, 6.4 g ofsodium hydroxide, and 500 mL of methanol were used. 24 grams of thealkylated product was then reacted with 50 g of 90%glycidylpropyltrimethylammonium chloride in methanol (1 L). The mixturewas stirred at reflux for 24 hours, after which it was cooled to roomtemperature and washed successively with water (three times using 2.5 Leach time). Vacuum drying afforded 22.4 g of dialkylated product.

[0095] Dialkylated products were prepared in an analogous manner byreplacing 1-iodododecane with 1-iododecane and 1-iodooctadecane,respectively, followed by alkylation withglycidylpropyltrimethylammonium chloride.

[0096] 21. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with Glycidylpropyltrimethylammonium Chloride AlkylatingAgent

[0097] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (5 g) was reacted with 11.63 g of 90%glycidylpropyltrimethylammonium chloride (1 mole equiv.) in methanol(100 mL). The mixture was stirred at 60° C. for 20 hours, after which itwas cooled to room temperature and washed successively with water (threetimes using 400 mL each time) and isopropanol (one time using 400 mL).Vacuum drying afforded 6.93 g of alkylated product.

[0098] Alkylated products were prepared in an analogous manner using50%, 200%, and 300% mole equiv of 90% glycidylpropyltrimethylammoniumchloride.

[0099] 22. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with (10-bromodecyl)trimethylammonium Bromide AlkylatingAgent

[0100] The first step is the preparation of (10-bromodecyl)trimethylammonium bromide as follows.

[0101] 1,10-dibromodecane (200 g) was dissolved in methanol (3 L) in a 5liter three neck round bottom flask fitted with a cold condenser (−5°C.). To this mixture was added aqueous trimethylamine (176 mL of a 24%aqueous solution, w/w). The mixture was stirred at room temperature for4 hours, after which is was heated to reflux for an additional 18 hours.At the conclusion of the heating period, the flask was cooled to 50° C.and the solvent removed under vacuum to leave a solid mass. Acetone (300mL) was added and the mixture stirred at 40° C. for 1 hour. The solidwas filtered off, resuspended in an additional portion of acetone (1 L),and stirred for 90 minutes.

[0102] At the conclusion of the stirring period, the solid was filteredand discarded, and the acetone fractions were combined and evaporated todryness under vacuum. Hexanes (about 1.5 L) were added and the mixturethen stirred for 1 hour, after which the solid was filtered off and thenrinsed on the filtration funnel with fresh hexanes. The resulting solidwas then dissolved in isopropanol (75 mL) at 40° C. Ethyl acetate (1500mL) was added and the temperature raised to about 50° C. to fullydissolve all solid material. The flask was then wrapped in towels andplaced in a freezer for 24 hours, resulting in the formation of solidcrystals. The crystals were filtered off, rinsed in cold ethyl acetate,and dried in a vacuum oven at 75° C. to yield 100.9 g of (10-bromodecyl)trimethyl-ammonium bromide as white crystals.

[0103] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (10 g) was suspended in methanol (300 mL). Sodiumhydroxide (3.3 g) was added and the mixture stirred until it dissolved.(10-bromodecyl) trimethylammonium bromide (20.7 g) was added and themixture was refluxed with stirring for 20 hours. The mixture was thencooled to room temperature and washed successively with methanol (twotimes using 1 L each time), sodium chloride) two times using 1 L of 1 Msolution each time), water (three times using 1 L each time), andisopropanol (one time using 1 L). Vacuum drying yielded 14.3 g ofalkylated product.

[0104] 23. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with (10-bromodecyl)trimethylammonium Bromide and1,10-dibromodecane Alkylating Agents

[0105] 1,10-dibromodecane (200 g) was dissolved in methanol (3 L) in a 5liter round bottom flask fitted with a cold condenser (−5° C.). To thismixture was added aqueous trimethylamine (220 mL of a 24% aqueoussolution, w/w). The mixture was stirred at room temperature for 4 hours,after which it was heated to reflux for an additional 24 hours. Theflask was then cooled to room temperature and found to contain 3350 mLof clear liquid.

[0106] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (30 g) was suspended in the clear liquid (2 L)and stirred for 10 minutes. Sodium hydroxide (20 g) was then added andthe mixture stirred until it had dissolved. Next, the mixture wasrefluxed with stirring for 24 hours, cooled to room temperature, and thesolid filtered off. The solid was then washed successively with methanol(one time using 10 L), sodium chloride (two times using 10 L of a 1 Msolution each time), water (three times using 10 L each time), andisopropanol (one time using 5 L). Vacuum drying afforded 35.3 g ofdialkylated product.

[0107] 24. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with (10-bromodecyl)trimethylammonium Bromide and1-bromodecane Alkylating Agents

[0108] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (10 g) was suspended in methanol (300 mL). Sodiumhydroxide (4.99 g) was added and the mixture stirred until it dissolved.(10-bromodecyl) trimethylammonium bromide prepared as described inExample 22 (20.7 g) and 1-bromodecane were added and the mixture wasrefluxed with stirring for 20 hours. The mixture was then cooled to roomtemperature and washed successively with methanol (two times using 1 Leach time), sodium chloride (two times using 1 L of a 1 M solution eachtime), water (three times using 1 L each time), and isopropanol (onetime using 1 L). Vacuum drying yielded 10.8 g of dialkylated product.

[0109] Dialkylated products were also prepared in analogous fashionusing different amounts of 1-bromodecane as follows: (a) 3.19 g1-bromodecane and 4.14 g sodium hydroxide to yield 11.8 g of dialkylatedproduct; (b) 38.4 g 1-bromodecane and 6.96 g sodium hydroxide to yield19.1 g of dialkylated product.

[0110] Dialkylated products were also prepared in analogous fashionusing the following combinations of alkylating agents: 1-bromodecane and(4-bromobutyl)trimethylammonium bromide; 1-bromodecane and(6-bromohexyl)trimethylammonium bromide; 1-bromodecane and(8-bromooctyl)trimethylammonium bromide; 1-bromodecane and(2-bromoethyl)trimethylammonium bromide; 1-bromodecane and(3-bromopropyl)trimethylammonium bromide; 1-bromohexane and(6-bromohexyl)trimethylammonium bromide; 1-bromododecane and(12-bromododecyl)trimethyl-ammonium bromide; and 1-bromooctane and(6-bromohexyl) trimethylammonium bromide.

[0111] 25. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with 11-bromo-1-undecanol Alkylating Agent

[0112] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (5.35 g) was suspended in methanol (100 mL).Sodium hydroxide (1.10 g) was added and the mixture stirred until itdissolved. 11-bromo-1-undecanol (5.0 g) was added and the mixture wasrefluxed with stirring for 20 hours, after which it was cooled to roomtemperature and washed successively with methanol (one time using 3 L),sodium chloride (two times using 500 mL of a 1 M solution each time),and water (three times using 1 L each time). Vacuum drying yielded 6.47g of alkylated product.

[0113] The reaction was also performed using 1.05 g sodium hydroxide and10 g 11-bromo-1-undecanol to yield 8.86 g of alkylated product.

[0114] 26. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with N-(2,3-epoxypropane)butyramide Alkylating Agent

[0115] The first step is the preparation of N-allyl butyramide asfollows.

[0116] Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuranwas added to a three neck round bottom flask equipped with athermometer, stir bar, and dropping funnel. The contents of the flaskwere then cooled to 15° C. in an ice bath while stirring. Allylamine(208.7 g, 3.65 mol) in 50 mL of tetrahydrofuran was then added slowlythrough the dropping funnel while maintaining stirring. Throughout theaddition, the temperature was maintained at 15° C. After addition wascomplete, stirring continued for an additional 15 minutes, after whichthe solid allylamine chloride precipitate was filtered off. The filtratewas concentrated under vacuum to yield 236.4 g of N-allyl butyramide asa colorless viscous liquid.

[0117] N-allyl butyramide (12.7 g, 0.1 mol) was taken into a 1 L roundbottom flask equipped with a stir bar and air condenser. Methylenechloride (200 mL) was added to the flask, followed by3-chloroperoxybenzoic acid (50-60% strength, 200 g) in five portionsover the course of 30 minutes and the reaction allowed to proceed. After16 hours, TLC analysis (using 5% methanol in dichloromethane) showedcomplete formation of product. The reaction mixture was then cooled andfiltered to remove solid benzoic acid precipitate. The filtrate waswashed with saturated sodium sulfite solution (two times using 100 mLeach time) and then with saturated dosium bicarbonate solution (twotimes using 100 mL each time). The dichloromethane layer was then driedwith anhydrous sodium sulfate and concentrated under vacuum to yield10.0 g of N-(2,3-epoxypropane) butyramide as a light yellow viscousliquid.

[0118] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (10 g, −80 sieved) and methanol (250 mL) wereadded to a 1 L round bottom flask, followed by N-(2,3-epoxypropane)butyramide (0.97 g, 0.0067 mol, 5 mol %) and then sodium hydroxidepellets (0.55 g, 0.01375 mol). The mixture was stirred overnight at roomtemperature. After 16 hours, the reaction mixture was filtered and thesolid washed successively with methanol (three times using 300 mL eachtime), water (two times using 300 mL each time), and isopropanol (threetimes using 300 mL each time. Vacuum drying at 54° C. overnight yielded9.0 g of the alkylated product as a light yellow powder.

[0119] Alkylated products based upon 10 mol %, 20 mol %, and 30 mol %N-(2, 3-epoxypropane) butyramide were prepared in analogous fashionexcept that (a) in the 10 mol % case, 1.93 g (0.013 mol)N-(2,3-epoxypropane) butyramide and 1.1 g (0.0275 mol) sodium hydroxidepellets were used to yield 8.3 g of alkylated product, (b) in the 20 mol% case, 3.86 g (0.026 mol) N-(2,3-epoxypropane) butyramide and 2.1 g(0.053 mol) sodium hydroxide pellets were used to yield 8.2 g ofalkylated product, and (c) in the 30 mol % case, 5.72 g (0.04 mol)N-(2,3-epoxypropane) butyramide and 2.1 g (0.053 mol) sodium hydroxidepellets were used to yield 8.32 g of alkylated product.

[0120] 27. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with N-(2,3-epoxypropane) Hexanamide Alkylating Agent

[0121] The first step is the preparation of N-allyl hexanamide asfollows.

[0122] Hexanoyl chloride (33 g, 0.25 mol) in 250 mL of tetrahydrofuranwas added to a three neck round bottom flask equipped with athermometer, stir bar, and dropping funnel. The contents of the flaskwere then cooled to 15° C. in an ice bath while stirring. Allylamine(28.6 g, 0.5 mol) in 200 mL of tetrahydrofuran was then added slowlythrough the dropping funnel while maintaining stirring. Throughout theaddition, the temperature was maintained at 15° C. After addition wascomplete, stirring continued for an additional 15 minutes, after whichthe solid allylamine chloride precipitate was filtered off. Thefiltration was concentrated under vacuum to yield 37 g of N-allylhexanamide as a colorless viscous liquid.

[0123] N-allyl hexanamide (16 g, 0.1 mol) was taken into a 1 L roundbottom flask equipped with a stir bar and air condenser. Methylenechloride (200 mL) was added to the flask, followed by3-chloroperoxybenzoic acid (50-60% strength, 200 g) in five portionsover the course of 30 minutes and the reaction allowed to proceed. After16 hours, TLC analysis (using 5% methanol in dichloromethane) showedcomplete formation of product. The reaction mixture was then cooled andfiltered to remove solid enzoic acid precipitate. The filtrate waswashed with saturated sodium sulfite solution (two times using 100 mLeach time) and then with saturated sodium bicarbonate solution (twotimes using 100 mL each time). The dichloromethane layer was then driedwith anhydrous sodium sulfate and concentrated under vacuum to yield14.2 g of N-(2,3-epoxypropane) hexanamide as a light yellow viscousliquid.

[0124] Poly(allylamine) crosslinked with epichlorohydrin prepared asdescribed in Example 4 (10 g, -80 sieved) and methanol (250 mL) wereadded to a 1 L round bottom flask, followed by N-(2,3-epoxypropane)hexanamide (4.46 g, 0.026 mol, 20 mol %) and then sodium hydroxidepellets (2.1 g, 0.053 mol). The mixture was stirred overnight at roomtemperature. After 16 hours, the reaction mixture was filtered and thesolid washed successively with methanol (three times using 300 mL eachtime), water (two times using 300 mL each time), and isopropanol (threetimes using 300 mL each time. Vacuum drying at 54° C. overnight yielded9.59 g of the alkylated product as a light yellow powder.

[0125] An alkylated product based upon 30 mol % N-(2,3-epoxypropane)hexanamide was prepared in analogous fashion except that 6.84 g (0.04mol) N-(2,3-epoxypropane) hexanamide was used to yield 9.83 g ofalkylated product.

[0126] 28. Alkylation of Poly(allylamine) Crosslinked withEpichlorohydrin with (6-Bromohexyl)trimethylammonium Bromide and1-bromodecane Alkylating Agent

[0127] To a 12-1 round bottom flask equipped with a mechanical stirrer,a thermometer, and a condenser is added methanol (5 L) and sodiumhydroxide (133.7 g). The mixture is stirred until the solid hasdissolved and crosslinked poly(allylamine) (297 g; ground to −80 meshsize) is added along with additional methanol (3 L). (6-Bromohexyl)trimethylammonium bromide (522.1 g) and 1-bromodecane (311.7 g) areadded and the mixture heated to 65° C. with stirring. After 18 hours at65° C. the mixture is allowed to cool to room temperature. The solid isfiltered off and rinsed by suspending, stirring for 30 minutes, andfiltering off the solid from: methanol, 12 L; methanol, 12L; 2 M aqueousNaCl, 22 L; 2 M aqueous NaCl, 22 L; deionized water, 22 L; deionizedwater, 22 L; deionized water, 22 L and isopropanol, 22 L. The solid isdried in a vacuum oven at 50° C. to yield 505.1 g of off-white solid.the solid is then ground to pass through an 80 mesh sieve.

[0128] Testing of Polymers

[0129] Preparation of Artificial Intestinal Fluid

[0130] Sodium carbonate (1.27 g) and sodium chloride (1.87 g) weredissolved in 400 mL of distilled water. To this solution was addedeither glycocholic acid (1.95 g, 4.0 mmol) or glycochenodeoxycholic acid(1.89 g, 4.0 mmol) to make a 10 mM solution. The pH of the solution wasadjusted to 6.8 with acetic acid. These solutions were used for thetesting of the various polymers.

[0131] Polymers were tested as follows.

[0132] To a 14 mL centrifuge tube was added 10 mg of polymer and 10 mLof a bile salt solution in concentrations ranging from 0.1-10 mMprepared from 10 mM stock solution (prepared as previously described)and buffer without bile salt, in the appropriate amount. The mixture wasstirred in a water bath maintained at 37° C. for three hours. Themixture was then filtered. The filtrate was analyzed for total 3-hydroxysteroid content by an enzymatic assay using 3a-hydroxy steroiddehydrogenase, as described below.

[0133] Enzymatic Assay for Total Bile Salt Content

[0134] Four stock solutions were prepared.

[0135] Solution 1—Tris-HCl buffer, containing 0.133 M Tris, 0.666 mMEDTA at pH 9.5.

[0136] Solution 2—Hydrazine hydrate solution, containing 1 M hydrazinehydrate at pH 9.5.

[0137] Solution 3—NAD solution, containing 7 mM NAD+ at pH 7.0.

[0138] Solution 4—HSD solution, containing 2 units/mL in Tris-HCl buffer(0.03 M Tris, 1 mM EDTA) at pH 7.2.

[0139] To a 3 mL cuvette was added 1.5 mL of Solution 1, 1.0 mL ofSolution 2, 0.3 mL of solution 3, 0.1 mL of Solution 4 and 0.1 mL ofsupernatant/filtrate from a polymer test as described above. Thesolution was placed in a UV-VIS spectrophotometer and the absorbance(O.D.) of NADH at 350 nm was measured. The bile salt concentration wasdetermined from a calibration curve prepared from dilutions of theartificial intestinal fluid prepared as described above.

[0140] All of the polymers previously described were tested in the abovemanner and all were efficacious in removing bile salts from theartificial intestinal fluid.

[0141] Use

[0142] The polymers according to the invention may be administeredorally to a patient in a dosage of about 1 mg/kg/day to about 10g/kg/day; the particular dosage will depend on the individual patient(e.g., the patient's weight and the extent of bile salt removalrequired). The polymer may be administrated either in hydrated ordehydrated form, and may be flavored or added to a food or drink, ifdesired to enhance patient acceptability. Additional ingredients such asother bile acid sequestrants, drugs for treating hypercholesterolemia,atherosclerosis or other related indications, or inert ingredients, suchas artificial coloring agents may be added as well.

[0143] Examples of suitable forms for administration include pills,tablets, capsules, and powders (e.g., for sprinkling on food). The pill,tablet, capsule, or powder can be coated with a substance capable ofprotecting the composition from the gastric acid in the patient'sstomach for a period of time sufficient to allow the composition to passundisintegrated into the patient's small intestine. The polymer may beadministered alone or in combination with a pharmaceutically acceptablecarrier substance, e.g., magnesium carbonate, lactose, or a phospholipidwith which the polymer can form a micelle.

[0144] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention as defined by the appended claims.

What is claimed is:
 1. The salt of an alkylated and crosslinked polymercomprising the reaction product of: (a) one or more crosslinkedpolymers, or salts and copolymers thereof having a repeat unit selectedfrom the group consisting of:

(NR—CH₂CH₂)_(n)  (2) and (NR—CH₂CH₂—NR—CH₂CH₂—NR—CH₂CHOH—CH₂)_(n)  (3)where n is a positive integer and each R, independently, is H or a C₁-C₈alkyl group; (b) at least one aliphatic alkylating agent, said reactionproduct characterized in that: (i) at least some of the nitrogen atomsin said repeat units unreacted with said alkylating agent; (ii) lessthan 10 mol % of the nitrogen atoms in said repeat units reacting withsaid alkylating agent forming quaternary ammonium units; and (iii) afixed positive charge and one or more counterions.
 2. The polymer saltof claim 1 wherein at least one of said counterions is Cl⁻, Br⁻, CHOSO₃⁻, HSO₄ ⁻, SO₄ ²⁻, HCO₃ ⁻, CO₃ ²⁻.
 3. The polymer salt of claim 1wherein said polymer is crosslinked by means of a multifunctionalcrosslinking agent, said agent being present in an amount from about0.5-25% by weight, based upon the combined weight of monomer andcrosslinking agent.
 4. The polymer salt of claim 1 wherein thecrosslinking agent comprises epichlorohydrin.
 5. The polymer salt ofclaim 1 wherein said alkylating agent has the formula RX where R is aC₁-C₂₀ alkyl, C₁-C₂₀ hydroxyalkyl, C₁-C₂₀ alkylammonium, or C₁-C₂₀alkylamido group and X is one or more electrophilic leaving groups. 6.The polymer salt of claim 5 wherein said alkylating agent comprises aC₁-C₂₀ alkyl halide.
 7. The polymer salt of claim 5 wherein saidalkylating agent comprises a C₁-C₂₀ alkyl halide ammonium salt.
 8. Thepolymer salt of claim 7 wherein said alkyl halide ammonium salt is aC₄-C₁₂ haloalkyl trimethylammonium salt.
 9. The polymer salt of claim 1wherein said polymer is reacted with at least two of said alkylatingagent, one of said alkylating agents has the formula RX where R is aC₁-C₂₀ alkyl group and X is one or more electrophilic leaving groups,and the other of said alkylating agents has the formula R′X where R′ isa C₁-C₂₀ alkyl ammonium group and X is one or more electrophilic leavinggroups
 10. The polymer salt of claim 9 wherein one of said alkylatingagents having the formula RX is an alkyl halide and the other of saidalkylating agents having the formula R′X is an alkyl halide ammoniumsalt.
 11. The polymer salt of claim 10 wherein said alkyl halide is aC₄-C₂₀ alkyl halide and said alkyl halide ammonium salt is a C₄-C₁₈alkyl halide ammonium salt.
 12. The polymer salt of claim 11 whereinsaid alkyl halide is a C₁₀ alkyl halide and said alkyl halide ammoniumsalt is a C₆ alkyl halide trimethyl ammonium salt.